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Much has been written about the general justifications for providing legal protection for trade marks — for example, it has been said that trade marks help to reduce consumer search costs, that they protect against the misappropriation of other traders’ labour and investment, and that they may provide traders with incentives to invest in the development of new marks. However, it is important not to conflate these justifications with the reasons for having registered trade mark systems. To the extent that this issue has been considered, the principal justification for registration that has been put forward is that trade mark registers act as an important source of public information. More specifically, trade mark registers provide information as to the signs that are protected in a given commercial sphere and as to matters such as initial ownership of trade marks and subsequent assignments thereof. Consequently, in order for a trade mark register to perform its function effectively, it is essential that it reflect as accurately as possible the marks that enjoy legal protection and that those consulting the register are able to rely on the information it conveys.
Vaccines have revolutionised the field of medicine, eradicating and controlling many diseases. Recent pandemic vaccine successes have highlighted the accelerated pace of vaccine development and deployment. Leveraging this momentum, attention has shifted to cancer vaccines and personalised cancer vaccines, aimed at targeting individual tumour-specific abnormalities. The UK, now regarded for its vaccine capabilities, is an ideal nation for pioneering cancer vaccine trials. This article convened experts to share insights and approaches to navigate the challenges of cancer vaccine development with personalised or precision cancer vaccines, as well as fixed vaccines. Emphasising partnership and proactive strategies, this article outlines the ambition to harness national and local system capabilities in the UK; to work in collaboration with potential pharmaceutic partners; and to seize the opportunity to deliver the pace for rapid advances in cancer vaccine technology.
Viloxazine ER (extended-release capsules; Qelbree®) is a nonstimulant medication, FDA-approved for ADHD in children (≥6 years) and adults. Efficacy and safety for children and adolescents were evaluated in one phase 2 [NCT02633527]and four phase 3 [NCT03247517, NCT03247556, NCT03247530, and NCT03247543], double-blind (DB), placebo-controlled trials that fed into a long-term, open-label extension (OLE) trial [NCT02736656]. Here we report the findings from this OLE trial.
Methods
Participants completing the DB trials were eligible for the OLE. Viloxazine ER was initiated at 100 mg/day (children) or 200 mg/day (adolescents) and adjusted (if needed) over a 12-week Dose-Optimization Period (up to 400 mg/day [children] or 600 mg/day [adolescents]). Maintenance treatment then continued up to 72 months. Safety assessments included adverse events (AEs), clinical laboratory tests, vital signs, ECG (12-lead), and the Columbia Suicide Severity Rating Scale (C-SSRS). Efficacy assessments included the ADHD Rating Scale, 4th (Phase 2) or 5th (Phase 3) Edition (ADHD-RS-IV/5), and the Clinical Global Impression-Improvement (CGI-I) scale. Efficacy was assessed relative to DB baseline at study visits ˜ 3 months apart. Two response measures, 50% improvement in ADHD-RS-IV/5 Total score and CGI-I score of 1-2, were also evaluated.
Results
1100 individuals (646 children; 454 adolescents; 66.5% male/33.5% female) received treatment. Median (range) exposure to viloxazine ER was 260 (1 to 1896) days. AEs were reported by 57.3% participants, most commonly (≥5%) nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%) decreased appetite (6.0%), and fatigue (5.7%). AEs were mostly mild or moderate in severity (3.9% reported any severe AE); AEs led to viloxazine ER discontinuation for 8.2%. The mean (SD) changes from DB baseline in ADHD-RS IV/5 Total score were -17.0 (14.18) (viloxazine ER) and -11.2 (13.19) (placebo) at the last DB study visit, 24.3 (11.96) at OLE Month 3, and 22.4 (13.62) at participants’ last OLE study visit. ADHD-RS-IV/5 and CGI-I responder rates each exceeded 65% at all OLE visits following Dose-Optimization.
Conclusions
The safety and efficacy of viloxazine ER were maintained with long-term use in children and adolescents with ADHD. No new safety concerns emerged, and efficacy results suggested potential for continued improvement over that seen during DB treatment.
To compare the incidence of surgical site infection (SSI) between cefazolin 3 g and 2 g surgical prophylaxis in patients weighing ≥120 kg that undergo elective colorectal surgery.
Methods:
A multicenter, retrospective cohort study was performed utilizing a validated database of elective colorectal surgeries in Michigan acute care hospitals. Adults weighing ≥120 kg who received cefazolin and metronidazole for surgical prophylaxis between 7/2012 and 6/2021 were included. The primary outcome was SSI, which was defined as an infection diagnosed within 30 days following the principal operative procedure. Multivariable logistic regression was used to identify variables associated with SSI; the exposure of interest was cefazolin 3 g surgical prophylaxis.
Results:
A total of 581 patients were included; of these, 367 (63.1%) received cefazolin 3 g, while 214 (36.8%) received 2 g. Patients who received cefazolin 3 g had less optimal antibiotic timing (324 [88.3%] vs 200 [93.5%]; P = .043) and a higher receipt of at least 1 of the prophylaxis antibiotics after incision (22 [6%] vs 5 [2.3%]; P = .043). There was no SSI difference between cefazolin 3 g and 2 g cohorts (23 [6.3%] vs 16 [7.5%], P = .574). When accounting for age, smoking status, and surgical duration, cefazolin 3 g was not associated with a reduction in SSI (adjOR, .64; 95%CI, .32–1.29).
Conclusions:
Surgical prophylaxis with cefazolin 3 g, in combination with metronidazole, was not associated with decreased SSI compared to 2 g dosing in obese patients undergoing elective colorectal surgery.
High-cost gene therapies strain the sustainability of healthcare budgets. Despite the potential long-term savings promised by certain gene therapies, realizing these savings faces challenges due to uncertainties regarding the treatment’s durability and a lesser-discussed factor: the true potential for cost offset. Our study aims to assess the cost-offset uncertainty for US Medicaid regarding recently approved gene therapies in hemophilia A and B.
Methods
The analysis used 2018 to 2022 Colorado Department of Health Care Policy & Financing data to determine direct costs of standard of care (factor replacement therapy or emicizumab). Cost-simulation models over five- and ten-year time horizons estimated Colorado Medicaid costs if patients switched to gene therapy (valoctocogene roxaparvovec or etranacogene dezaparvovec) versus maintaining standard of care. Patients were included if aged 18 and over with ICD-10-CM codes D66 (hemophilia A) and D67 (hemophilia B). In the base case, severe hemophilia A was defined as requiring greater than or equal to six yearly factor VIII or emicizumab claims and moderate/severe hemophilia B requiring greater than or equal to four factor IX replacement therapy claims annually.
Results
Annual standard-of-care costs were USD426,000 (SD USD353,000) for hemophilia A and USD546,000 (SD USD542,000) for hemophilia B. Valoctocogene roxaparvovec (hemophilia A) had incremental costs of USD880,000 at five years and −USD481,000 at 10 years. Sensitivity analysis revealed a 23 percent chance of break-even within five years and 48 percent within 10 years. Etranacogene dezaparvovec (hemophilia B) showed incremental costs of USD429,000 at five years and −USD2,490,000 at 10 years. Simulation indicated a 32 percent chance of break-even within five years and 59 percent within 10 years. Varying eligibility (≥4 to ≥15 standard-of-care claims) notably affected break-even; for example, valoctocogene roxaparvovec: 40 percent to 77 percent chance of break-even in 10 years.
Conclusions
Our study highlights significant cost variation in the standard of care of patients eligible for gene therapies, adding to the uncertainty surrounding cost estimation and highlighting the importance of addressing this factor in risk-sharing agreements. The impact of varying eligibility criteria on cost offsets emphasizes the importance of carefully defining eligibility when using real-world data in the context of health technology assessment.
Patients with hematological malignancies are at high risk of infections due to both the disease and the associated treatments. The use of immunoglobulin (Ig) to prevent infections is increasing in this population, but its cost effectiveness is unknown. This trial-based economic evaluation aimed to compare the cost effectiveness of prophylactic Ig with prophylactic antibiotics in patients with hematological malignancies.
Methods
The economic evaluation used individual patient data from the RATIONAL feasibility trial, which randomly assigned 63 adults with chronic lymphocytic leukemia, multiple myeloma, or lymphoma to prophylactic Ig or prophylactic antibiotics. The following two analyses were conducted to estimate the cost effectiveness of the two treatments over the 12-month trial period from the perspective of the Australian health system:
(i) a cost-utility analysis (CUA) to assess the incremental cost per quality-adjusted life-year (QALY) gained using data collected with the EuroQol 5D-5L questionnaire; and
(ii) a cost-effectiveness analysis (CEA) to assess the incremental cost per serious infection prevented (grade ≥3) and per infection prevented (any grade).
Results
The total cost per patient was significantly higher in the Ig arm than in the antibiotic arm (difference AUD29,140 [USD19,000]). There were non-significant differences in health outcomes between the treatment arms: patients treated with Ig had fewer QALYs (difference −0.072) and serious infections (difference −0.26) than those given antibiotics, but more overall infections (difference 0.76). The incremental cost-effectiveness from the CUA indicated that Ig was more costly than antibiotics and associated with fewer QALYs. In the CEA, Ig costed an additional AUD111,262 (USD73,000) per serious infection prevented, but it was more costly than antibiotics and associated with more infections when all infections were included.
Conclusions
These results indicate that, on average, Ig prophylactic treatment may not be cost effective compared with prophylactic antibiotics for the group of patients with hematological malignancies recruited to the RATIONAL feasibility trial. Further research is needed to confirm these findings in a larger population and over the longer term.
The new software package OpenMx 2.0 for structural equation and other statistical modeling is introduced and its features are described. OpenMx is evolving in a modular direction and now allows a mix-and-match computational approach that separates model expectations from fit functions and optimizers. Major backend architectural improvements include a move to swappable open-source optimizers such as the newly written CSOLNP. Entire new methodologies such as item factor analysis and state space modeling have been implemented. New model expectation functions including support for the expression of models in LISREL syntax and a simplified multigroup expectation function are available. Ease-of-use improvements include helper functions to standardize model parameters and compute their Jacobian-based standard errors, access to model components through standard R $ mechanisms, and improved tab completion from within the R Graphical User Interface.
Reconciling registration and use as mechanisms by which rights can be acquired in a trade mark is inherently difficult. The federal Australian registered trade mark system is built around a hybrid of a registration-based and a use-based model of protection. While it is perfectly possible to defend such a dual model, the two means of acquiring trade mark rights rest on very different logics. In the event of a conflict between a registered mark and a mark that has been used for some time the question of which should take precedence is not necessarily capable of being determined a priori. The relationship between registration and use is mediated by a number of provisions of the Trade Marks Act 1995 (Cth). In this article we focus on one such provision, s 58A, a relatively recent addition to the legal landscape.
Through a close analysis of s 58A, focusing on court decisions and decisions of the Trade Marks Office that have applied this provision, we demonstrate that s 58A has the potential to operate in an entirely unsatisfactory manner. We then use problems with s 58A as a vehicle to explore the relationship between use-based and registration-based rights generally, suggesting a new conceptual framework that might serve to guide future discussion of how the relationship between registration and use ought to be mediated.
Using the assumption of randomly parallel tests and concepts from generalizability theory, three signal/noise ratios for domain-referenced tests are developed, discussed, and compared. The three ratios have the same noise but different signals depending upon the kind of decision to be made as a result of measurement. It is also shown that these ratios incorporate a definition of noise or error which is different from the classical definition of noise typically used to characterize norm-referenced tests.
Abacs approximating the product-moment correlation for both explicit and implicit selection are presented. These abacs give accuracy to within .01 of the corresponding analytic estimate.
A method is presented for constructing a covariance matrix Σ*0 that is the sum of a matrix Σ(γ0) that satisfies a specified model and a perturbation matrix,E, such that Σ*0=Σ(γ0) +E. The perturbation matrix is chosen in such a manner that a class of discrepancy functions F(Σ*0, Σ(γ0)), which includes normal theory maximum likelihood as a special case, has the prespecified parameter value γ0 as minimizer and a prespecified minimum δ A matrix constructed in this way seems particularly valuable for Monte Carlo experiments as the covariance matrix for a population in which the model does not hold exactly. This may be a more realistic conceptualization in many instances. An example is presented in which this procedure is employed to generate a covariance matrix among nonnormal, ordered categorical variables which is then used to study the performance of a factor analysis estimator.
To describe the effect of a Stenotrophomonas maltophilia (SM) respiratory culture nudge on antibiotic use in colonized patients.
Design:
IRB-approved quasi-experiment.
Setting:
Five acute-care hospitals in Michigan.
Patients:
Adult patients with SM respiratory culture between 01/01/2022 and 01/27/2023 (pre-nudge) and 03/27/2023–12/31/2023 (post-nudge). Patients with active community/hospital/ventilator-acquired pneumonia or who received SM-targeted antibiotics at the time of culture were excluded.
Methods:
A nudge comment was implemented 02/2023 stating: “S. maltophilia is a frequent colonizer of the respiratory tract. Clinical correlation for infection is required. Colonizers do not require antibiotic treatment.” The primary outcome was no treatment with SM-therapy; secondary outcomes were treatment with SM-therapy ≥72 hrs, length of stay, and in-hospital, all-cause mortality. Safety outcomes included antibiotic-associated adverse drug events (ADEs).
Results:
94 patients were included: 53 (56.4%) pre- and 41 (43.6%) post-nudge. Most patients were men (53, 56.4%), had underlying lung disease (61, 64.8%), and required invasive ventilatory support (70, 74.5%). Eleven (11.7%) patients resided in a long-term care facility. No treatment with SM therapy was observed in 13 (23.1%) pre- versus 32 (78.0%) post-nudge patients (P <0.001). There were no differences in secondary outcomes. Antibiotic-associated ADEs were common (33/41, 76%) in patients who received ≥72hrs of SM-therapy: fluid overload (18, 44%), hyponatremia (17, 42%), elevated SCr (12, 29%), hyperkalemia (5, 12%). After adjustment for confounders, post-nudge was associated with 11-fold increased odds of no treatment with SM-therapy (adjOR, 11.72; 95%CI, 4.18–32.83).
Conclusions:
A targeted SM nudge was associated with a significant reduction in treatment of colonization, with similar patient outcomes. SM-treated patients frequently developed antibiotic-associated ADEs.
In the context of climate change, the impacts of extreme weather events are increasingly recognised as a significant threat to mental health in the UK. As clinicians and researchers with an interest in mental health, we have a collective responsibility to help understand and mitigate these impacts. To achieve this, however, it is vital to have an appreciation of the relevant policy and regulatory frameworks. In this feature article, a collaboration amongst mental health and policy experts, we provide an overview of the integration of mental health within current climate policies and regulations in the UK, including gaps and opportunities. We argue that current policy and regulatory frameworks are lacking in coverage, ambition, detail and implementation, as increases in weather extremes and their negative impacts on mental health outpace action. For example, across current national and local climate policies, there is almost no reference to the impacts of extreme weather events on mental health. Whilst alarming, this provides scope for future research to fill evidence gaps and inform policy and regulatory change. We call for mental health and policy experts to work together to improve our understanding of underlying mechanisms and develop practical interventions, helping to bring mental health within climate policy and regulatory frameworks.
People with type 2 diabetes (T2D) are more likely to experience binge eating than the general population, which may interfere with their diabetes management. Guided self-help (GSH) is one of the recommended treatment options for binge eating disorder, but there is currently a lack of evidenced treatment for binge eating in individuals living with T2D. The aims of this pilot study were to test the feasibility and acceptability of recruiting and delivering the adapted, online Working to Overcome Eating Difficulties GSH intervention to adults with T2D and binge eating. The intervention comprises GSH materials presented online in seven sections delivered over 12 weeks, supported by a trained Guide. Twenty-two participants were recruited in a case series design to receive the intervention and we interviewed four Guides and five participants afterwards. We measured binge eating, mental wellbeing, quality of life and weight at pre-post and 12-week follow-up. Results showed a significant reduction in binge eating at the end of the intervention, which continued to improve at follow-up. Before the programme, 92 % of participants scored above cut-off for binge eating. This reduced to 41 % post-intervention and no-one at follow-up. These changes were accompanied by significant improvements in depression, anxiety and small changes in eating disorder symptoms. Participants reported making better lifestyle choices, eating more mindfully and having increased self-confidence. The study shows preliminary evidence for online GSH tailored to the needs of individuals with T2D as a feasible and acceptable approach to improving binge eating, diabetes management and mental wellbeing.
Latinx populations are underrepresented in clinical research. Asking Latinx research participants about their research experiences, barriers, and facilitators could help to improve research participation for these populations.
Methods:
The Salud Estres y Resilencia (SER) Hispano cohort study is a longitudinal cohort study of young adult Latinx immigrants whose design and conduct were tailored for their study population. We administered the Research Participant Perception Survey (RPPS) to SER Hispano participants to assess their experiences in the study. We describe overall results from the RPPS and compare results of surveys administered to SER Hispano participants via email versus telephone.
Results:
Of 340 participants who were contacted with the RPPS, 142 (42%) responded. Among respondents, 53 (37%) responded by initial email contact; and 89 (63%) responded by subsequent phone contact. The majority of respondents were between 35 and 44 years of age (54%), female (76%), and of Cuban origin (50%). Overall, research participants expressed high satisfaction with their research experience; 84% stated that they would “definitely” recommend research participation to friends and family, with no significant difference by method of survey administration (P = 0.45). The most common factor that was chosen that would influence future research participation was having summary results of the research shared with them (72%).
Conclusion:
We found that culturally tailored studies can be good experiences for Latinx research participants; and we found that use of the RPPS can be administered successfully, particularly when administered by more than one method, including telephone, to evaluate and to improve research experiences for this population.
Psychotic symptoms in adolescence are associated with social adversity and genetic risk for schizophrenia. This gene–environment interplay may be mediated by personality, which also develops during adolescence. We hypothesized that (i) personality development predicts later Psychosis Proneness Signs (PPS), and (ii) personality traits mediate the association between genetic risk for schizophrenia, social adversities, and psychosis.
Methods
A total of 784 individuals were selected within the IMAGEN cohort (Discovery Sample-DS: 526; Validation Sample-VS: 258); personality was assessed at baseline (13–15 years), follow-up-1 (FU1, 16–17 years), and FU2 (18–20 years). Latent growth curve models served to compute coefficients of individual change across 14 personality variables. A support vector machine algorithm employed these coefficients to predict PPS at FU3 (21–24 years). We computed mediation analyses, including personality-based predictions and self-reported bullying victimization as serial mediators along the pathway between polygenic risk score (PRS) for schizophrenia and FU3 PPS. We replicated the main findings also on 1132 adolescents recruited within the TRAILS cohort.
Results
Growth scores in neuroticism and openness predicted PPS with 65.6% balanced accuracy in the DS, and 69.5% in the VS Mediations revealed a significant positive direct effect of PRS on PPS (confidence interval [CI] 0.01–0.15), and an indirect effect, serially mediated by personality-based predictions and victimization (CI 0.006–0.01), replicated in the TRAILS cohort (CI 0.0004–0.004).
Conclusions
Adolescent personality changes may predate future experiences associated with psychosis susceptibility. PPS personality-based predictions mediate the relationship between PRS and victimization toward adult PPS, suggesting that gene–environment correlations proposed for psychosis are partly mediated by personality.
Society of Thoracic Surgeons Congenital Heart Surgery Database is the largest congenital heart surgery database worldwide but does not provide information beyond primary episode of care. Linkage to hospital electronic health records would capture complications and comorbidities along with long-term outcomes for patients with CHD surgeries. The current study explores linkage success between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health record data in North Carolina and Georgia.
Methods:
The Society of Thoracic Surgeons Congenital Heart Surgery Database was linked to hospital electronic health records from four North Carolina congenital heart surgery using indirect identifiers like date of birth, sex, admission, and discharge dates, from 2008 to 2013. Indirect linkage was performed at the admissions level and compared to two other linkages using a “direct identifier,” medical record number: (1) linkage between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health records from a subset of patients from one North Carolina institution and (2) linkage between Society of Thoracic Surgeons data from two Georgia facilities and Georgia’s CHD repository, which also uses direct identifiers for linkage.
Results:
Indirect identifiers successfully linked 79% (3692/4685) of Society of Thoracic Surgeons Congenital Heart Surgery Database admissions across four North Carolina hospitals. Direct linkage techniques successfully matched Society of Thoracic Surgeons Congenital Heart Surgery Database to 90.2% of electronic health records from the North Carolina subsample. Linkage between Society of Thoracic Surgeons and Georgia’s CHD repository was 99.5% (7,544/7,585).
Conclusions:
Linkage methodology was successfully demonstrated between surgical data and hospital-based electronic health records in North Carolina and Georgia, uniting granular procedural details with clinical, developmental, and economic data. Indirect identifiers linked most patients, consistent with similar linkages in adult populations. Future directions include applying these linkage techniques with other data sources and exploring long-term outcomes in linked populations.